Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice

Authors

Weijun Ou, Chapman University
Yuu Ohno, Keck Graduate Institute
Joshua Yang, Chapman University
Devaraj V. Chandrashekar, Chapman University
Tamara Abdullah, Chapman University
Jiahong Sun, Chapman University
Riley Murphy, Chapman UniversityFollow
Chuli Roules, Chapman University
Nataraj Jagadeesan, Chapman University
David H. Cribbs, University of California, Irvine
Rachita K. Sumbria, Chapman UniversityFollow

Document Type

Article

Publication Date

10-16-2022

Abstract

Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer’s disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood–brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (Aβ) 1-42, soluble-oligomeric Aβ, and microgliosis; however, only TfRMAb-TNFR reduced Aβ peptides, Thioflavin-S-positive Aβ plaques, and insoluble-oligomeric Aβ and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematology- or iron-dysregulation in aged APP/PS1 mice.

Comments

This article was originally published in Pharmaceutics, volume 14, issue 10, in 2022. https://doi.org/10.3390/pharmaceutics14102200

Recommended Citation

Ou W, Ohno Y, Yang J, et al. Efficacy and safety of a brain-penetrant biologic TNF-α inhibitor in aged APP/PS1 mice. Pharmaceutics. 2022;14(10):2200. https://doi.org/10.3390/pharmaceutics14102200

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This work is licensed under a Creative Commons Attribution 4.0 License.